KR20090110255A - Transdermal drug administration device - Google Patents

Abstract

PURPOSE: A transdermal drug administering apparatus is provided to stably release drug from the apparatus. CONSTITUTION: A transdermal drug administering apparatus comprises: an area(first part, 1) where a matrix layer is positioned near a support layer or the other area(second part, 2) where the matrix layer is positioned far from the support layer. The first part contains moisture absorbent polymer of which weigh density is higher than that of second apart. The moisture absorbent polymer is not dissolved in the matrix layer. The matrix layer contains a drug.

Description

Drug transdermal administration device {TRANSDERMAL DRUG ADMINISTRATION DEVICE}

The present invention relates to a drug transdermal administration device comprising a support layer and a matrix layer provided on at least one side thereof.

Drug transdermal administration devices have many advantages, such as the possibility of absorption of the drug in the gastrointestinal tract, the avoidance of the hepatic first pass effect, the benefit for patients having difficulty swallowing the drug, the prevention of administration manure, and the like. As such, the superiority of drug transdermal administration devices has been noted as dosage forms, and various drug transdermal administration devices have been developed. It has also been proposed to construct a drug transdermal administration device by combining a plurality of membranes according to the purpose. Literature related to such drug transdermal administration devices is, for example, as follows.

Drug transdermal administration devices provided with a polymer-blend matrix have been disclosed (Patent Document 1). The matrix disclosed herein is merely a polymer blend. Thus, the matrix has a homogenized layer. It is difficult for such devices to have high control over drug release.

In addition, a drug transdermal administration device having a multilayer structure has also been disclosed (Patent Documents 2 and 3). However, in the multilayer structure of the device disclosed herein, since the adhesive layer does not contain a water absorbent polymer at a specific site, the pharmaceutical component in the multilayer structure may move to the adhesive layer due to diffusion or penetration during long-term storage, so that the multilayer structure of the multilayer structure is Become uniform. Thus, the sufficient effect expected from the drug transdermal administration device cannot be achieved.

Prior art literature

Patent Literature

Patent Document 1: U.S. Patent 5,656,286

Patent Document 2: JP-A-56-125311

Patent document 3: JP-A-59-207149

In view of the above mentioned situation, it is an object of the present invention to provide a drug transdermal administration device which can easily control drug release.

The present inventors have diligently studied the drug transdermal administration device comprising a support layer and a matrix layer provided on at least one side of the support layer, wherein the matrix layer is located proximal to the support layer (hereinafter referred to as first portion) and support layer. A region located distally from, hereinafter referred to as a second portion, wherein at least the first portion comprises a water absorbent polymer, wherein the water absorbent polymer of the first portion is less than the water absorbent polymer of the second portion Higher weight concentrations] have been found to be highly controllable for drug release from the device, thus completing the present invention. Accordingly, the present invention provides the following.

[1] a drug transdermal administration device comprising a support layer and a matrix layer provided on at least one side of the support layer, wherein the matrix layer is located proximal to the support layer (hereinafter referred to as first portion) and distal from the support layer. A region located hereinafter, hereinafter referred to as a second portion, wherein at least the first portion comprises a water absorbent polymer, wherein the water absorbent polymer of the first portion has a weight concentration greater than that of the second portion. Higher).

[2] The drug transdermal administration device according to the above [1], wherein the water absorbent polymer is not dissolved in the matrix layer.

[3] The drug transdermal administration device according to the above [1] or [2], wherein the matrix layer contains a drug.

[4] The drug transdermal administration device according to any one of the above [1] to [3], wherein the matrix layer contains an adhesive substance.

[5] The drug transdermal administration device according to any one of the above [1] to [4], wherein the matrix comprises a first layer comprising at least a first portion and a second layer comprising a second portion.

[6] The drug transdermal administration device according to any one of [1] to [5], further comprising a release liner laminated on the skin contact surface of the matrix.

According to the drug transdermal administration device of the present invention, drug release can be highly controlled. In particular, by controlling the weight concentrations of the water absorbent polymer of the first portion and the water absorbent polymer of the second portion, drug release from the device can be freely controlled. Thus, there is no need to adjust the weight concentration of other components of the matrix layer, such as drugs, at one site of the matrix layer. Thus, the drug transdermal administration device can be flexibly designed and the drug can be released stably from the device. If the water absorbent polymer is insoluble in the matrix, the polymer does not dissolve in the matrix layer, so that even when the device is stored for a long time, the polymer is not readily available from one site. Thus, drug release from the device can be controlled even after long term storage of the device.

The invention is described in detail below.

The drug transdermal administration device of the present invention has a matrix layer on at least one side of the support layer. The matrix layer comprises at least drugs, water absorbent polymers and other tacky materials.

The "adhesive material" is not particularly limited as long as it is possible to conveniently join each member constituting the device and adhere the matrix layer to the skin. A substance having adhesion at room temperature (25 ° C.) is preferable because each member constituting the device can be conveniently bonded and the matrix layer is adhered to the skin. In general, it is possible to use polymers, ie those containing pressure-sensitive adhesives. An adhesive here means an adhesive polymer composition comprising an elastomer or elastomer which is itself tacky and the thickeners mentioned below. The amount of the pressure-sensitive adhesive in the matrix layer is not particularly limited, but is preferably 60 to 90% by weight, more preferably 70 to 85% by weight. If the amount is 60% by weight or more, sufficient adhesion strength of the matrix layer to the skin is ensured. If the amount is 90% by weight or less, a flexible design of the matrix layer is ensured.

Examples of such an adhesive include an acrylic adhesive including an acrylic polymer; Rubbers including rubber elastomers such as styrene-diene-styrene block copolymers (eg, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, etc.), polyisoprene, polyisobutylene, polybutadiene, and the like adhesive; Silicone pressure sensitive adhesives including silicone elastomers such as silicone rubber, dimethylsiloxane base, diphenylsiloxane base and the like; Bityl ether pressure-sensitive adhesives such as polyvinyl methyl ether, polyvinyl ethyl ether, polyvinyl isobutyl ether, and the like; Vinyl ester pressure sensitive adhesives such as vinyl acetate-ethylene copolymer and the like; Polyester adhesives made from carboxylic acid components (eg, dimethyl terephthalate, dimethylisophthalate, dimethylphthalate, etc.) and polyhydric alcohol components (eg, ethylene glycol, etc.) are included. These may be used alone or in mixture of two or more thereof. In terms of skin stickiness, hydrophobic pressure-sensitive adhesives and anhydrous pressure-sensitive adhesives are preferable. From the standpoint of the balance of ease of use, adhesion properties, stability and safety, a rubber adhesive containing polyisobutylene is more preferred.

When the thickener is included in the pressure-sensitive adhesive, examples of the thickener include polybutene, petroleum resin (e.g., aromatic petroleum resin, aliphatic petroleum resin), terpene resin, rosin resin, coumaroneindene resin, styrene resin (e.g., styrene resin, α- Methylstyrene), hydrogenated petroleum resins (eg, acyclic saturated hydrocarbon resins), and the like. Of these, polybutene is preferred because of its good storage stability. One or more thickeners can be used in combination.

The amount of thickener is preferably 30 to 90% by weight of the total weight of the adhesive, more preferably 50 to 70% by weight. When the amount of the thickener is less than 30% by weight, the adhesiveness may be poor, and when the amount of the thickener is greater than 90% by weight, the adhesive layer tends to be stiff and the skin stickiness tends to be reduced.

Hereinafter, when the polyisobutylene is contained in the matrix layer, the adhesiveness necessary for the matrix layer and essential polyisobutylene are referred to as the first polyisobutylene, and various purposes such as increasing the adhesive force of the matrix layer and the like. The polyisobutylene further added in is called the second polyisobutylene.

The first polyisobutylene is not particularly limited, but the viscosity average molecular weight is preferably 1,600,000 to 6,500,000, more preferably 2,000,000 to 6,000,000, and most preferably 3,000,000 to 5,000,000. If the viscosity average molecular weight is less than 1,600,000, the adhesive strength of the matrix layer can be reduced, possibly leading to an adhesive residue due to desorption. If the viscosity average molecular weight exceeds 6,500,000, compatibility with other components decreases and the uniformity as an adhesive may not be maintained, which may lead to adhesive residue on the skin when the device is detached from the skin.

When the second polyisobutylene is added to enhance the adhesion of the matrix layer, the viscosity average molecular weight of the second polyisobutylene is preferably 30,000 to 100,000, more preferably 40,000 to 80,000, most preferably 50,000 to 50,000. 60,000. When the viscosity average molecular weight is less than 30,000, the amount added may be limited because it weakens the adhesion strength. When the said viscosity average molecular weight exceeds 100,000, the molecular weight of 2nd polyisobutylene is substantially the same as the molecular weight of 1st polyisobutylene, and it may be difficult to show an adhesive force improvement effect.

The ratio (a / b) x 100 (% by weight) of the weight (a) of the second polyisobutylene to the weight (b) of the first polyisobutylene is not particularly limited, but is preferably 50 to 200% by weight. 75 to 150% by weight is more preferred, and 90 to 110% by weight is most preferred. When the ratio of the second polyisobutylene is 50% by weight or more, the effect of the second polyisobutylene is sufficiently exhibited. If the above-mentioned ratio is 200% by weight or less, sufficient adhesion of the matrix layer is ensured.

When the second polyisobutylene is added to further increase the adhesive strength of the matrix layer, it is preferable that the viscosity average molecular weight of the second polyisobutylene is higher than the viscosity average molecular weight of the first polyisobutylene.

The viscosity average molecular weight herein is obtained by calculating the Staudinger index (J ₀ ) from the capillary flow time of a Uberode viscometer at 20 ° C. by the Schulz-Blaschke equation and determining from the following equation using the J ₀ value:

(equation)

J ₀ = η _sp / c ( ^{1 +} 0.31η _sp ) cm ³ / g (Schulz-Blaschke equation)

η _sp = t / t ₀ -1

t: flow time of the solution (by Hagenbach-couette correction)

t ₀ : Solvent flow time (by Hagenbach-couette correction)

c: concentration of solution (g / cm ³ )

J ₀ = 3.06 X 10 ^-2 Mv ^0.65

Mv: viscosity average molecular weight

By water absorbent polymer is meant herein a polymeric material that swells by absorbing moisture in an amount of at least its weight. The water absorbent polymer is not particularly limited, but polyvinyl alcohol, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, methoxyethylenemaleic anhydride copolymer, methacrylic acid polymer or polysaccharide sodium alginate, ammonium alginate, carbox Bosimethylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylethylcellulose, methylcellulose, soluble starch, carboxymethylamylose, dextrin, etc., other pectin, agar powders, etc. Vegetable rubbers such as gum arabic, tragacanth rubber, xanthan rubber and the like, starch grafting acrylate and the like can be mentioned. These may be used alone or in mixture of two or more thereof.

It is preferable that the water absorbent polymer is insoluble in the matrix even after water absorption. A water absorbent polymer that is insoluble in the matrix is referred to below as the "matrix layer-insoluble material". The matrix layer-insoluble material is a component other than a drug which does not dissolve in the matrix layer at room temperature (25 ° C.) but is dispersed in a solid state. The matrix layer insoluble material is insoluble in the matrix layer and therefore does not readily migrate in the matrix. Thus, the weight concentration of the matrix layer insoluble material in the matrix layer does not easily change even after long term storage of the device. The matrix layer insoluble material is swollen by absorption of moisture such as sweat and the like to provide the effect of releasing the drug from the matrix layer. This effect is higher at higher weight concentrations of the matrix layer insoluble material, resulting in faster drug release rates. Since the weight of the matrix layer insoluble matter does not change, stable release properties can be maintained even after long term storage. For example, if the weight concentration of the matrix layer insoluble material is higher than the weight concentration at other sites, the release rate of the drug from certain sites of the matrix layer is faster than the release rates at other sites. In particular, when the matrix layer insoluble material absorbs moisture, this tendency is prominent and in this case it may be advantageous to practice the invention.

The matrix layer insoluble material is substantially insoluble in the matrix (substantially insoluble, the matrix insoluble material itself is insoluble in the matrix but can be somewhat soluble by degradation under harsh conditions such as thermal history during device manufacture, long term storage of the device, etc. Is not particularly limited, and a water absorbent material is preferable for the above-mentioned reasons. In this aspect, the material is preferably crosslinked polyvinylpyrrolidone.

Crosslinked polyvinylpyrrolidone can be obtained by copolymerization of N-vinyl-2-pyrrolidone and multifunctional monomers. Examples of multifunctional monomers that can be used include di (meth) acrylates such as hexamethylene glycol di (meth) acrylate, ethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, and the like; Tri (meth) acrylates such as trimethylolpropane tri (meth) acrylate and the like; And tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate; Polyallyl compounds such as diethylene glycol bisallylcarbonate, triallylglycerol, triallyl cyanurate and the like; Polymaleimide compounds such as ethylene bismaleimide and the like. Alternatively, divinylbenzene, methylenebisacrylamide, ethylidenebisvinylpyrrolidone, divinylketone, butadiene, isoprene and the like can also be used.

It is preferable that the amount of the multifunctional monomer which can be copolymerized is 0.1 to 10 mol% of the total amount of the monomers. If it is less than 0.1 mol%, there is a possibility that the resulting crosslinked polyvinylpyrrolidone is difficult to dissolve or swell in the elastomer and act as a crosslinked form. If the amount of the multifunctional monomer exceeds 10 mol%, the properties of vinylpyrrolidone are diluted and cannot be easily expressed.

Crosslinked polyvinylpyrrolidone is commercially available under the trade names Kollidon CL, Kollidon CL-M (all from BASF), Polyplasdone (ISB), crospovidone (GOKYO TRADING CO., LTD) and the like. Considering the effect on the amount of participation, the smaller the particle size is the maximum surface area is effective. In this respect Kollidon CL-M is preferred.

1 is a schematic cross-sectional view of a transdermal administration device of the present invention. In FIG. 1, 1 is the matrix layer insoluble material of the second part, 2 is the matrix layer insoluble material of the first part, 3 is the first part, 4 is the second part, 5 is the support layer, and the arrow is the drug Indicates the direction of release. The difference in arrow size indicates the difference in the rate of drug release, with the large arrow indicating a faster rate of drug release than the smaller arrow.

1 will now be described in more detail. The matrix layer includes a first portion and a second portion. The first portion and the second portion contain a matrix layer insoluble material, and the weight concentration of the first portion is higher than the weight concentration of the second portion. The rate of drug release from the first portion is faster than the rate of drug release from the second portion. The first portion is located closer to the support layer than the second portion. In a typical transdermal administration device, the drug is released rapidly at the first stage of transdermal administration, and then the amount of release of the drug is gradually reduced, so that in some cases the drug is not stably transdermally administered. However, in the present invention, since a second portion having a low weight concentration matrix layer insoluble component exists near the skin contact surface, the rate of drug release from the skin contact surface of the matrix layer does not become too high in the first stage of transdermal administration, so that The risk of side effects from drug administration can be reduced.

The matrix insoluble material may be contained only in the first part and the weight concentration of the matrix layer insoluble material in the second part may be 0%. However, it is preferred that the matrix insoluble material is contained in both the first part and the second part.

In order to achieve similar drug release rates in the early stages of transdermal administration and in the later stages of transdermal administration, the weight concentration of the matrix insoluble substance of the first portion is preferably 1.5 times or more, more preferably 2.0 times or more, 2.5 times or more of the second portion. It is most preferable that it is above. The upper limit of the ratio is not particularly limited, but in order to keep the matrix insoluble substance stably in the matrix layer, it is preferably 10 times or less.

The weight concentration of the matrix insoluble material in the first portion is generally 5 to 35% by weight, preferably 10 to 30% by weight, more preferably 15 to 25% by weight. Concentrations of at least 5% by weight favor the retention of the highly polar organic liquid component and concentrations of up to 35% by weight favor the fixing properties for the support layer.

The weight concentration of the matrix insoluble material in the second part is generally 1 to 15% by weight, preferably 3 to 12% by weight, more preferably 5 to 10% by weight. Concentrations of 1% by weight or more are advantageous for drug release and concentrations up to 15% by weight are advantageous for skin adhesion.

The drug is not particularly limited, and a drug that can be administered to an animal (eg, a mammal such as a human) through the skin, that is, a transdermal absorbent drug is preferable. Specific examples of drugs include general anesthetics, sleep sedatives, antiepileptic drugs, antipyretic analgesic drugs, anti-dizziness drugs, antipsychotic drugs, local anesthetics, skeletal muscle relaxants, autonomic drugs, antispasmodic drugs, antiparkinsonism drugs, antihistamines, cardiovascular drugs, arrhythmia Drugs, diuretics, hypertension drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, arteriosclerosis drugs, circulatory drugs, antitussive expectorants, hormonal drugs, external medications for battery bottles, analgesic-antipruritic-hemophilic-anti-inflammatory drugs, parasites Skin disease drugs, bleeding stop drugs, gout treatment drugs, diabetic drugs, anti-malignancies, antibiotics, chemotherapy drugs, anesthetics, smoking cessation aids, and the like.

The drug content is not particularly limited as long as the effect of the transdermal absorbent drug is obtained and the adhesive properties of the adhesive are not impaired. The drug content is preferably 0.1 to 10% by weight of the adhesive, more preferably 0.1 to 7% by weight. If the drug content is less than 0.1% by weight, the therapeutic effect may not be sufficient, and if it exceeds 10% by weight, skin irritation may occur and be an economically disadvantageous content.

If the matrix layer insoluble material is a water absorbent polymer, hydrophilic drugs are preferred. Hydrophilic drugs herein have a partition coefficient (1-octanol / water), ie, logPow, of 0.5 to 5.5. In order to fully acquire the effect of this invention, it is preferable that logPow of a drug is 1.0-5.0, and it is more preferable that it is 3.0-5.0. If the logPow of the drug is less than 0.5, the drug is highly hydrophilic. Even with the present invention, such drugs can be precipitated as crystals in the matrix layer. On the other hand, if the logPow of the drug exceeds 5.5, the drug is highly hydrophobic and less likely to precipitate as crystals in the matrix layer. In this case, the advantages of the present invention are not so high.

LogPow herein is an index indicating the hydrophilicity or hydrophobicity of the compound, which is calculated by the logPow calculation software Cache (registered trademark) manufactured by FUJITSU LIMITED. For the measurement (calculation) of logPow, the formula of the compound is entered into the calculation software to calculate logPow.

If the drug is a solid at room temperature, ie a drug with a melting point of at least 100 ° C. is advantageous in the present invention. Although the upper limit of melting | fusing point is not specifically limited, It is preferable that it is 1000 degrees C or less practically.

The melting point of drug herein means the value measured by the following method.

Device: Melting point measuring device manufactured by MIYAMOTO RIKEN IND JAPAN

Measuring method: According to Japanese Pharmacopoeia, 15th edition, melting point measuring method, first method, the thermometer reading is taken as the melting point when the sample is liquefied in the capillary tube and no solid is observed at all.

It is advantageous to be able to form a first layer containing the first portion and a second layer containing the second portion in the matrix layer so that the rate of drug release from the skin contacting surface can be highly controlled.

2 shows a schematic cross section of an embodiment of the invention. In this embodiment, the matrix layer consists of the first layer 30 and the second layer 40. It is also possible to further form a third layer or the like. The first layer 30 containing the first portion 20 of the matrix layer is laminated on one side of the support layer 50, and the second layer 40 containing the second portion 10 of the matrix layer is deposited thereon. Lay on top. The first layer and the second layer contain the matrix layer insoluble component, and the first layer contains the matrix layer insoluble component in an amount equal to or preferably higher than the amount of the matrix layer insoluble component contained in the second layer. In this regard, the weight concentration can be applied. In this embodiment, since the first layer consists of the first part and the second layer consists of the second part, it is possible to stabilize the drug release rate since the above mentioned drug release rate is surely controlled.

The composition of the first layer and the second layer is not particularly limited, but the drug concentration is preferably the same in order to stabilize the quality of the device, since the drug may move due to equilibration during the manufacturing step of the device, during storage of the device, and the like. For the same reason, it is preferable that the mixing ratio of the tacky materials of the first layer and the second layer is the same. In particular, high concentrations of the drug in the matrix layer may be separated (crystallized / leaked) from the matrix, so care must be taken in changing the concentration. In the present invention, since the concentrations of the water absorbent polymers of the first layer and the second layer are different, it is preferable that the amount of the adhesive material of the first layer and the second layer only change to an amount corresponding to the concentration of the water absorbent polymer.

If desired, the matrix layer may contain an organic liquid component as a tacky material. The organic liquid component can plasticize the matrix layer, control the adhesion to the adhesion site and control the transdermal absorption of the drug that may be contained in the matrix layer.

Examples of the organic liquid component include plasticizers such as diisopropyladipate, diacetyl sebacate and the like; Glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, and the like, fats and oils such as olive oil, castor oil, squalene, lanolin, and the like; Hydrocarbons such as liquid paraffin and squalene; Various surfactants; Alcohols such as polyhydric alcohols (eg, glycerol, etc.) or monoalcohols (eg, octyldodecanol, oleyl alcohol, ethoxylated stearyl alcohol, etc.); Oleic acid monoglycerides, caprylic acid monoglycerides; Glycerol monoesters such as glycerol esters or lauryl acid monoglycerides such as glycerol diesters, glycerol triesters and mixtures thereof; Fatty acid esters such as ethyl laurate, isopropyl myristate, isotridecyl myristate, octyl palmitate, isopropyl palmitate, ethyl oleate and diisopropyl adipate; Fatty acids such as oleic acid and caprylic acid; And N-methylpyrrolidone, 1,3-butanediol and the like. Among them, alcohols, glycerol esters and fatty acid esters are preferred in view of the transdermal absorption of physiologically active ingredients.

The amount of the organic liquid component in the matrix layer is not particularly limited, but the total weight thereof is preferably 5 to 25% by weight, more preferably 10 to 20% by weight relative to the total weight of the pressure-sensitive adhesive layer. If the amount is 5% by weight or more, sufficient adhesion strength of the matrix layer to the skin is ensured. If the amount is 20% by weight or less, the adhesive strength of the matrix layer can be ensured, and the design flexibility of the matrix layer is increased.

The support layer is not particularly limited, but is substantially impermeable to drugs and the like, that is, does not allow a decrease in the content of the active ingredient drugs, additives and the like in the matrix layer by preventing the active ingredient in the matrix layer from being lost from the back side through the support layer. It is preferable.

Examples of the support layer include a single film such as polyester, nylon, saran (registered trademark), polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, Surlyn (registered trademark), metal foil, and the like. Or laminated films and the like. The thickness of the support layer is generally 10 to 500 mu m, preferably 10 to 200 mu m.

The support layer is preferably one which is a laminated film of a non-porous plastic film and a porous film made from the above-mentioned materials in order to improve the adhesion (fixing force) between the support layer and the matrix layer. In this case, the matrix layer is preferably formed on the porous film side.

As such a porous film, what can improve the fixing force with respect to a matrix layer is used. Specific examples include paper, wovens, nonwovens, knits, machine perforated sheets, and the like. Among them, paper, woven fabric, and nonwoven fabric are particularly preferable in view of handleability.

In consideration of improvements in fixation force, flexibility and adhesion of drug transdermal administration devices, a porous film having a thickness of 10 to 200 μm is used. In thin products such as plaster or adhesive tape, those having a thickness of 10 to 100 µm are used.

When woven or nonwoven is used as the porous film, the fabric weight is preferably set to 5 to 30 g / m ² , more preferably 6 to 15 g / m ² . In the present invention, the most preferred support layer is a polyester film [preferably a poly (ethylene terephthalate) film] of 1.5 to 6 [mu] m thick and a polyester [preferably a poly (with a fabric weight of 6 to 12 g / m ² ). Ethylene terephthalate)] is a laminated film of a nonwoven fabric.

The drug transdermal administration device of the present invention preferably has a release liner that is laminated to the skin contact surface of the matrix layer and protects the surface until use.

The release liner is not particularly limited as long as the light peeling property can be sufficiently secured. Examples thereof include films such as polyester, polyvinyl chloride, polyvinylidene chloride, poly (ethylene terephthalate), etc., which have been subjected to peeling treatment by applying a silicone resin, a fluorine resin, or the like to the surface in contact with the matrix layer, and high-quality paper and glossy paper. , Laminated films of paper such as polyolefin and high-quality paper, glossy paper and the like. The thickness of the release liner is generally 10 to 200 mu m, preferably 25 to 100 mu m.

The release liner of the present invention is preferably made of polyester (particularly poly (ethylene terephthalate)) resin in terms of barrier properties and cost. In addition, from the viewpoint of handleability, a release liner having a thickness of about 25 to 100 μm is more preferable.

The device may take the form of a sheet or tape.

The drug transdermal administration device of the present invention that does not include a multilayer structure comprises mixing a water absorbent polymer, a drug, a sticky material at room temperature, and other starting materials to provide a composition for forming a matrix layer and placing the composition on a liner or support layer. It may be prepared by a method comprising the step of laminating on. For example, the device can be manufactured by applying centrifugal force in a direction substantially perpendicular to the support layer to uniformly distribute the water absorbent polymer in the support layer.

In addition, the drug transdermal administration device of the present invention having a multi-layer structure comprises the steps of dispersing or dissolving the adhesive, the water absorbent polymer, the drug and the organic liquid component in a solvent, applying the resulting first blend to the liner, the liner And drying and applying to the liner material, applying the second partial blend to the liner separately, and drying the liner and applying to the first partial sheet previously prepared.

Example

The invention is explained in more detail below with reference to examples which are not to be construed as limiting. Hereinafter, "part" means "part by weight".

[1] Preparation of Composition A for Matrix Layer Formation

Polyisobutylene A (16.3 parts, viscosity average molecular weight 4,000,000), polyisobutylene B (16.3 parts, viscosity average molecular weight 55,000), polybutene (48.8 parts) as thickener, dipropylene glycol (1.8 parts), propylene glycol mono N-hexane in an appropriate amount to a mixture of laurate (1.5 parts), oleyl alcohol (5 parts), isopropyl myristate (5 parts) and crosslinked polyvinylpyrrolidone (Kollidon CL-M, 5 parts) Was added and the mixture was mixed with estradiol (0.3 parts) to give Composition A for matrix layer formation.

[2] Preparation of Composition B for Formation of Matrix Layer

Polyisobutylene A (15.3 parts), polyisobutylene B (15.3 parts), the above-mentioned thickener (45.8 parts), dipropylene glycol (1.8 parts), propylene glycol monolaurate (1.5 parts), oleyl alcohol (5 parts), n-hexane was added to a mixture of isopropyl myristate (5 parts) and crosslinked polyvinylpyrrolidone (Kollidon CL-M, 10 parts), and the mixture was added to estradiol (0.3 parts). Further mixed with to obtain composition B for matrix layer formation.

[3] Preparation of Composition C for Matrix Layer Formation

Polyisobutylene A (14.3 parts), polyisobutylene B (14.3 parts), the aforementioned thickeners (42.8 parts), dipropylene glycol (1.8 parts), propylene glycol monolaurate (1.5 parts), oleyl alcohol (5 parts), n-hexane is added to a mixture of isopropyl myristate (5 parts) and crosslinked polyvinylpyrrolidone (Kollidon CL-M, 15 parts), and the mixture is estradiol (0.3 parts) Further mixed with to obtain composition C for matrix layer formation.

In the above-mentioned composition A for forming a matrix layer, a composition for forming a matrix layer, and a composition for forming a matrix layer C, the weight parts of each component except n-hexane are comprehensively described in Table 1.

Composition A for Matrix Layer Formation Composition B for Matrix Layer Formation Composition C for forming a matrix layer Estradiol 0.3 0.3 0.3 Crosslinked polyvinylpyrrolidone 5 10 15 Dipropylene glycol 1.8 1.8 1.8 Propylene Glycol Monolaurate 1.5 1.5 1.5 Oleyl alcohol 5 5 5 Isopropyl myristate 5 5 5 Polyisobutylene A 16.3 15.3 14.3 Polyisobutylene B 16.3 15.3 14.3 Thickener 48.8 45.8 42.8

Example 1

The composition C for forming a matrix layer was applied to a polyester film (thickness 75 μm) so as to have a thickness of 80 μm after drying, and dried and applied to a polyester film (thickness 12 μm). Furthermore, the composition A for matrix layer formation was apply | coated to the polyester film (75 micrometers in thickness) so that thickness might be 80 micrometers after drying, and it applied to the dry film, and obtained the drug transdermal administration apparatus of 160 micrometers in thickness.

Comparative Example 1

The composition B for forming a matrix layer was applied to a polyester film (thickness 75 μm) so as to have a thickness of 80 μm after drying, and dried and applied to a polyester film (thickness 12 μm). Furthermore, the composition B for matrix layer formation was apply | coated to a polyester film (75 micrometers in thickness) so that thickness might be 80 micrometers after drying, and it applied to the dry film, and obtained the drug transdermal administration apparatus of 160 micrometers in thickness.

Experimental Example 1

Tack release testing was conducted according to US Pharmacopeia 26, <724> Drug Release, Transdermal Delivery System-General Drug Release Standard. The solution released at 1, 2, 3, 6, 10, 24, 28, 32, 48, 52, 56, 72, 76, 80 hours from the start of the test was recovered. The solution was filtered through a membrane filter, quantified by high performance liquid chromatography (HPLC) and the amount of estradiol released was measured. The release rate was calculated from the amount of estradiol released within a predetermined time relative to the estradiol content in the test adhesive. The result is shown in FIG.

It is clear from FIG. 3 that the initial release rate of the drug was suppressed in Example 1 (FIG. 3, ES-146) of the present invention compared to Comparative Example 1 (FIG. 3, ES-147). It is also clear that the drug has been stably released from the device even after a long time.

This application is based on Japanese Patent Application No. 2008-106314 (filed April 16, 2008), the contents of which are hereby incorporated by reference in their entirety.

1 shows a schematic cross-sectional view of one embodiment of a drug transdermal administration device.

2 illustrates a schematic cross-sectional view of one embodiment of a drug transdermal administration device.

3 is a graph showing the results of Experimental Example 1. FIG.

Symbol Description

1 Matrix Layer Insoluble Material of Second Part

2 Matrix Layer Insoluble Material of First Part

3 first part

4 second part

5 support layer

10 Matrix layer insoluble material of the second part

20 Matrix Layer Insoluble Material of First Part

First layer of 30 matrix layers

Second layer of 40 matrix layer

50 support layer

Claims (6)

A drug transdermal administration device comprising a support layer and a matrix layer provided on at least one side of the support layer, wherein the matrix layer is a region located proximal to the support layer (hereinafter referred to as a first portion) and a region located distal from the support layer. (Hereinafter referred to as a second portion), wherein at least the first portion comprises a water absorbent polymer, and wherein the water absorbent polymer of the first portion has a higher weight concentration than the water absorbent polymer of the second portion Drug transdermal administration device. The device of claim 1, wherein the water absorbent polymer is insoluble in the matrix layer. The drug transdermal administration device according to claim 1 or 2, wherein the matrix layer comprises a drug. The device of claim 1, wherein the matrix layer comprises an adhesive material. The device of claim 1, wherein the matrix comprises a first layer comprising at least a first portion and a second layer having a second portion. The device of claim 1, further comprising a release liner laminated to the skin contacting surface of the matrix layer.

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